Human Primary Airway Basal Cells Display a Continuum of Molecular Phases from Health to Disease in Chronic Obstructive Pulmonary Disease

Am J Respir Cell Mol Biol. 2021 Jul;65(1):103-113. doi: 10.1165/rcmb.2020-0464OC.


Airway basal cells are crucial for regeneration of the human lung airway epithelium and are believed to be important contributors to chronic obstructive pulmonary disease (COPD) and other lung disorders. To reveal how basal cells contribute to disease and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and NGFR (nerve-growth factor receptor) expression. The basal cell population was found to be molecularly and functionally heterogeneous, in contrast to cultured basal cells. In addition, significant differences were found, such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single-cell RNA sequencing on primary basal cells from healthy donors and patients with Global Initiative for Chronic Obstructive Lung Disease stage IV COPD, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response-related genes GADD45B and AHSA1, together with with genes involved in the response to hypoxia, such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.

Keywords: COPD; basal cell; human primary tissue; whole RNA sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation / metabolism
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Humans
  • Keratin-14 / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Molecular Chaperones / metabolism
  • Nerve Tissue Proteins / metabolism
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Receptors, Nerve Growth Factor / metabolism
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology


  • AHSA1 protein, human
  • Antigens, Differentiation
  • GADD45B protein, human
  • KRT14 protein, human
  • Keratin-14
  • Molecular Chaperones
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Receptors, Nerve Growth Factor